ERK promotes hydrogen peroxide-induced apoptosis through caspase-3 activation and inhibition of Akt in renal epithelial cells.

Abstract

Reactive oxygen species, including hydrogen peroxide (H(2)O(2)), are generated during ischemia-reperfusion and are critically involved in acute renal failure. The present studies examined the role of the extracellular signal-regulated kinase (ERK) pathway in H(2)O(2)-induced renal proximal tubular cells (RPTC) apoptosis. Exposure of RPTC to 1 mM H(2)O(2) resulted in apoptosis and activation of ERK1/2 and Akt. Pretreatment with the specific MEK inhibitors, U0126 and PD98059, or adenoviral infection with a construct that encodes a negative mutant of MEK1, protected cells against H(2)O(2)-induced apoptosis. In contrast, expression of constitutively active MEK1 enhanced H(2)O(2)-induced apoptosis. H(2)O(2) induced activation of caspase-3 and phosphorylation of histone H2B at serine 14, a posttranslational modification required for nuclear condensation, which also were blocked by ERK1/2 inhibition. Furthermore, blockade of ERK1/2 resulted in an increase in Akt phosphorylation and blockade of Akt potentiated apoptosis and diminished the protective effect conferred by ERK inhibition in H(2)O(2)-treated cells. Although Z-DEVD-FMK, a caspase-3 inhibitor, was able to inhibit histone H2B phosphorylation and apoptosis, it did not affect ERK1/2 phosphorylation. We suggest that ERK elicits apoptosis in epithelial cells by activating caspase-3 and inhibiting Akt pathways and elicits nuclear condensation through caspase-3 and histone H2B phosophorylation during oxidant injury.

• Authors: Shougang Zhuang, Yan Yan, Rebecca A Daubert, Jiahuai Han, Rick G Schnellmann
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 292 Issue 1 Pg. F440-7 (Jan 2007) ISSN: 1931-857X [Print] United States
• PMID: 16885155 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chromones
• Enzyme Inhibitors
• Histones
• Morpholines
• Oxidants
• Tetrazolium Salts
• Thiazoles
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Hydrogen Peroxide
• Phosphatidylinositol 3-Kinases
• Oncogene Protein v-akt
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases
• Caspase 3
• thiazolyl blue

Topics

• Adenoviridae (drug effects, enzymology)
• Animals
• Apoptosis (drug effects)
• Caspase 3 (physiology)
• Cell Nucleus (drug effects, enzymology)
• Chromones (pharmacology)
• Enzyme Activation (physiology)
• Enzyme Inhibitors (pharmacology)
• Epithelial Cells (drug effects, enzymology)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Female
• Histones (metabolism)
• Hydrogen Peroxide (toxicity)
• Kidney (drug effects, enzymology)
• Kidney Tubules, Proximal (enzymology, pathology)
• Morpholines (pharmacology)
• Oncogene Protein v-akt (antagonists & inhibitors)
• Oxidants (toxicity)
• Phosphatidylinositol 3-Kinases (metabolism)
• Rabbits
• Tetrazolium Salts
• Thiazoles
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors)